Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the iPS cells and reprogramming technologies in medical science. While iPS cells are expected to open new era providing enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this symposium, the pre-clinical investigations of cell therapy for SCI using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo are outlined.

The aim of stem cell therapy for Parkinson's disease (PD) is to reconstruct local synapse formation and/or induce the release of dopamine and cytokines from grafted cells in the putamen. Fetal ventral-midbrain cells are reported to relieve the neurological symptoms of PD patients. However, not only embryonic stem cells (ESCs), but also induced pluripotent stem cells (iPSCs) are expected to provide an alternative donor cell population because of their capacity for self-renewal and pluripotency. A protocol to generate dopaminergic (DA) neurons from ESCs and iPSCs has been developed, and human ESCs were proven to function in the brain of rat and monkey PD models. The next step will be the isolation of DA neurons as a donor cell population for a safe and efficient transplantation.

The hemophagocytic syndrome(HPS) after the hematopoietic stem cell transplantation(SHCT) may be triggered by the reactivation of virus such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV) under immunosuppressive state. The present case was a 17-year old man who was diagnosed as B lymphoblastic leukemia. Bone marrow aspiration showed 96.4% of lymphoblasts with positive for CD19 and CD20, negative for CD66 and POX, and dot staining for PAS. E2A/PBX1 chimeric mRNA was positive as assessed by RT-PCR method. He received three courses of induction chemotherapy followed by allo-bone marrow transplantation (BMT) from his sister, but had a relapse three months after allo-BMT. He received allo peripheral blood-SCT (PBSCT) from his mother. The hematopoietic cells successfully engrafted, but the mixed chimerism of 2 donors persisted. On day 149, he had a fever, and hemophagocytosis was found by bone marrow aspiration. EBV genomic DNA was detected for 1.62 x 10(3) copies. CMV and fungus were negative in blood. On day 165, the patient had been observed disturbance of consciousness, neck stiffness, and died on day 170 due to multiple organ failure. Autopsy examination showed infiltration of CD20+ leukemic cells into the perivascular space of cerebrum, brainstem and spinal cord, with hemophagocytosis by CD6+ macrophages. In situ hybridization of EB-virus encoded small RNA (EBER) confirmed EBV infection of B-lymphoblastic cells infiltrated in the cerebrum. HPS was considered to be triggered by the reactivation of EBV, due to hematopoietic dysfunction based on long-term immunosuppressive treatment and mixed chimerism derived from a HSCT from 2 donors.

Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases.

Injuries to articular cartilage do not heal spontaneously, and when left untreated, result in the diffuse degeneration of cartilage. Autologous chondrocyte transplantation has been performed to treat focal articular cartilage defects, but the repaired tissue includes fibrous tissue. Healing with hyaline cartilage has been difficult to achieve. The generation of induced pluripotent stem (iPS) cells has enabled us to rejuvenate somatic cells and provide them with pluripotency. This technology may contribute to producing hyaline cartilage. In addition, fibroblasts can be converted toward chondrogenic cells by directed reprogramming technology. Research aimed at the realization of cartilage regeneration using cell reprogramming technologies is underway.